mmg_233_2014_genetics_genomicsfandomcom-20200215-history
Relaxation response and molecular genetics
Introduction Relaxation response is the polar opposite of the fight or flight response, serving as a counterpart to stress reactions. For thousands of years humans have actively sought to reduce chronic stress through mind-body interventions like yoga and prayer. Elicitation of the relaxation response has been shown to be effective in counteracting the adverse clinical effects of stress in disorders that include hypertension, anxiety, insomnia, diabetes, rheumatoid arthritis, and aging. The RR is elicited when an individual focuses on a single word, phrase, or sound as a method of departing from the train of everyday thought. Elicitation of the RR brings about certain biochemical changes in the body, including decreased O2 consumption, CO2 elimination, blood pressure, heart, and respiratory rate, and norepinephrine responsivity. Additionally eliciting the RR has been linked with increased heart rate variability and alterations in cortical and subcortical brain regions. Sustained expression changes in genes relating to oxidative phosphorylation, antigen processing and presentation, and apoptosis were identified in both short- and long-term RR practitioners when compared to novices. To gauge gene expression, blood samples were taken from beginner RR practitioners listening to a RR-eliciting audio sequence. Systems biology and interactive network analyses were utilized to examine focus gene hubs of RR. Identification of these hubs, which are focal points or critical molecules in broad networks of interacting genes, could serve as a basis for further investigation. The study provides scientific rationale for daily practitioners of RR elicitation. Methods Study Design The study in question utilized both prospective and cross-sectional features. The prospective aspect of the study involved 26 healthy subjects with no prior experience in the field of RR elicitation. These novices served as their own controls. The study subjects underwent 8 weeks of RR-eliciting training. The cross-sectional element of the study involved enrolling 26 health subjects with prior experience in the field of RR elicitation. Study Intervention Novices trained weekly with an expert clinician, practicing various RR-eliciting techniques including diaphragmatic breathing, body scan, mantra repetition, and mindfulness meditation while passively ignoring intrusive thoughts. A 20-minutes audio CD that guided listeners through the same practices while at home. Data Collection Blood samples and biological measures were collected when subjects attended morning laboratory sessions, during which the novices and experts listened to a 20-minutes RR-eliciting CD and the "N2" group of short-term practicioners listened to a health-education CD as a control. Data/Measurements Process Procedures Total RNA from peripheral blood mononuclear cells (PBMCs) in the blood samples was isolated. Real-time exhaled FeNO, an indicator of vascular dilation and a player in the immune response, was measured using a rapid response chemoluminescent Nitric Oxide Analyzer. Results The data indicated that RR leads to qualitative and quantitative temporal transcriptome changes. The study also showed that, in the short term, RR elicits distinct patterns of differential gene expression. Gene set enrichment analysis (GSEA) data showed that RR had a progressive effect on energy metabolism and inflammation pathways. IMmune response and telomere maintenance related pathways are affected in long-term RR practicioners. Systems biology analyses show upregulated progressive changes in mitochondrial function as a result of RR elicitation. Downregulated gene expression changes induced by RR are linked to alteration of NF-κB-dependent pathways that impact inflammation and immune response. Discussion Some of the first molecular mechanisms underlying RR-induced physiological response were provided by the study. Analysis of the transcriptome data showed that gene expression was modulated in both short- and long-term practitioners compared to novices. Genes impacting biological pathways responsible for energy metabolism, electron transport chain, biological oxidation and insulin secretion were identified to have a direct link to RR elicitation. More specifically, the systems biology analysis identified insulin (INS) and ATP synthase subunit gamma (ATP5C1) as top focus hubs. This is important because ATP synthase is central to ATP production, which in turn is a key determinant do secretion of insulin from B-cells in response to glucose. Mutations in ATP synthase have been shown to induce oxidative stress and impaired insulin secretion from B cells. The investigators postulated that upregulation of the ATP synthase pathway may play a central role in translating the beneficial effects of the RR. The down regulated pathways linked to the inflammatory response, including the transciption factors NF-κB and RELA, TNFR2, IL7 and TCR signaling. Downregulation of NF-κB may lead to the oxidative stress, insulin resistance, and apoptosis. NF-κB has been put forth as a potential bridge between psychosocial stress and oxidative cellular activation. In summary, the study concluded that RR practices induced upregulation of ATPase and insulin function. RR induced downregulation of NF-κB pathways with effects on upstream and downstream targets that may mitigate oxidative stress. The findings suggest that RR practice, by promoting "mitochondrial resiliancy," may be important at the cellular level for the health benefits associated with reducing psychososcial stress. References Bhasin, M.K., Dusek, J. A., Chang, B.-H., Joseph, M. G., Denninger, J. W., Fricchione, G.L., . . . Libermann, T. A. (2013). Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. PloS one, 8(5), e62817. doi: 10.1371/journal.pone.0062817